The treatment of patients with or at risk of developing ischemic syndromes with doses of an HMG-CoA reductase inhibitor to lower total and LDL cholesterol is known. This is done in order to restore endogenous vascular endothelium-dependent activities including, but not limited to vasodilatory responses modulating vascular tone and blood flow, antiadherent properties of the blood vessel wall, and anticoagulation of platelets (International Publication Number WO 95/13063).
There is evidence from animal models that compounds which inhibit the enzyme, acyl-coenzyme A:cholesterol acyltransferase (ACAT) will be effective anti-atherosclerotic agents, (Curr. Med. Chem., 1994;1:204-225). It is well-established that when the majority of cholesterol in plasma is carried on apolipoprotein B-containing lipoproteins, such as low-density lipoproteins (LDL-C) and very-low-density lipoproteins (VLDL-C), the risk of coronary artery disease in man is increased (Circulation, 1990;81:1721-1733). Conversely, high levels of cholesterol carried in high-density lipoproteins (HDL-C) is protective against coronary artery disease (Am. J. Med., 1977;62:707-714). Thus, a drug which reduces the levels of atherogenic LDL-C and VLDL-C and elevates levels of protective HDL-C will produce a less atherogenic lipoprotein profile and thus a beneficial effect on atherosclerotic disease and its complications. This beneficial effect was demonstrated in man in the Helsinki Heart Study with the lipid regulator gemfibrozil which decreased LDL-C, increased HDL-C, and reduced the incidence of coronary artery disease (N. Engl. J. Med., 1987;317:1237-1245).